An Active-Targeted ZIF8-Based Nanotheranostic Platform for Ultrasound Imaging-Guided Synergistic Therapy of Triple-Negative Breast Cancer

Xiaoxiao Li,1 Qi Zhou,2 Shaobo Duan,3 Linlin Zhang,2 Zesheng Li,2 Si Chen,2 Yue Yuan,2 Yuanyuan Liu,2 Yanghui Li,2 Xiguo Cai,4 Yuzhou Wang,5 Lianzhong Zhang1,3,4 1Department of Ultrasound, Henan University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, 450003, People’s Republic of China; 2Department of Ultrasound, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, 450003, People’s Republic of China; 3Department of Ultrasound, Henan Provincial International Joint Laboratory of Ultrasonic Nanotechnology and Artificial Intelligence in Precision Theragnostic Systems, Zhengzhou, 450003, People’s Republic of China; 4Henan Provincial Clinical Research Center for Rehabilitation Medicine, Zhengzhou, 450003, People’s Republic of China; 5College of Materials Engineering, Henan University of Engineering, Zhengzhou, 450000, People’s Republic of ChinaCorrespondence: Lianzhong Zhang, Department of Ultrasound, Henan University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, 450003, People’s Republic of China, Email [email protected] Yuzhou Wang, College of Materials Engineering, Henan University of Engineering, Zhengzhou, 450000, People’s Republic of China, Email [email protected]: To address the therapeutic challenges associated with triple-negative breast cancer (TNBC), we developed a folic acid-polyethylene glycol-modified ZIF8-based nanotheranostic platform (FA-PEG@ZIF8@CIP) designed to integrate synergistic sonodynamic therapy, chemotherapy, and immune activation for enhanced antitumor treatment.Methods: FA-PEG@ZIF8@CIP was constructed as a folic acid-polyethylene glycol-functionalized ZIF8 nanoplatform for the delivery of ciprofloxacin. In this system, ciprofloxacin acted as both a sonosensitizer and a chemotherapeutic agent, while the ZIF8 carrier provided pH-responsive release behavior in the acidic tumor microenvironment. The platform was further evaluated for its physicochemical properties, cellular uptake, antitumor efficacy, immune activation, and ultrasound imaging performance through a series of in vitro and in vivo experiments.Results: FA-PEG@ZIF8@CIP exhibited favorable tumor-targeting capability and potent antitumor activity. Under ultrasound irradiation, the platform markedly enhanced reactive oxygen species (ROS) generation, leading to effective tumor cell killing. In addition, it induced immunogenic cell death (ICD), as evidenced by enhanced calreticulin exposure, HMGB1 translocation, and extracellular ATP release. These effects further promoted dendritic cell maturation and increased cytotoxic T-lymphocyte infiltration within tumor tissues, indicating activation of antitumor immune responses. The proportions of CD8+ T cells in tumor tissues and spleen increased to 18.7% and 14.6%, respectively, corresponding to approximately 3.0-fold and 2.9-fold increases over the PBS group. The antitumor efficacy of FA-PEG@ZIF8@CIP+US was 4.21-fold higher than that of PBS. Moreover, the platform demonstrated effective ultrasound imaging capability, supporting its application for imaging-guided therapy. Collectively, these findings suggest that FA-PEG@ZIF8@CIP exerts therapeutic effects through the coordinated actions of sonodynamic therapy, chemotherapy, and immune modulation.Conclusion: This multifunctional nanosystem enables the integration of diagnosis and therapy and represents a promising strategy for TNBC treatment. By combining targeted delivery, pH-responsive drug release, ultrasound imaging, and synergistic therapeutic effects within a single platform, FA-PEG@ZIF8@CIP may offer a valuable approach for improving theranostic outcomes in TNBC.Keywords: metal-organic frameworks, folic acid response, immunogenic cell death, sonodynamic therapy, breast cancer theranostics